Herpes simplex viruses (HSV) are human pathogens which cause a variety of disease states including cold sores, eye and genital infections, life-threatening neonatal infections, and encephalitis. HSV is also capable of establishing latent infections in ganglia. The strains designated HSV-1 (oral) and HSV-2 (genital) are members of the family Herpesviridae and are classified in the subfamily alphahexpesvirinae and the genus simplex virus. The viruses have an enveloped double-stranded DNA genome of 150 kilobases (kb) including at least seventy-two open reading frames which encode at least eleven glycoproteins. The genomes of HSV-1 and HSV-2 exhibit extensive homology in regions which are known to encode proteins responsible for antigenic specificity and/or biological activity.
Upon infection, several vital glycoproteins act singly or in concert to bind HSV to a susceptible cell and trigger direct fusion between the virion envelope and the cell membrane. Glycoprotein D (gD) of HSV is a component of the virion envelope which plays an essential role in HSV entry into susceptible mammalian cells. The evidence to date suggests that gD binds to a cellular molecule, possibly the mannose-6-phosphate receptor, following the initial interaction of HSV glycoproteins gC and gB with heparan sulfate proteoglycans. The interaction between gD and its receptor may stabilize the virus-cell complex prior to membrane fusion which is mediated by other essential glycoproteins such as gB, gH, and gL. See Sisk et al., J. Virol., 68(3): 766-775 (1994) and Tat-Singer et al., J. Virol., 69(7): 4471-4483 (1995). The nucleotide sequence of the Patton strain of HSV-1 gD (gD-1) (SEQ ID NO: 3) was first reported in Watson et al., Science, 218:381-384 (1982). The strain 333 HSV-2 gD (gD-2) was described in Muggeridge et al., J. Virol., 64(8): 3617-3626 (1990). The nucleotide sequence of the strain 333 gD-2 gene is set out in SEQ ID NO: 14 herein.
The HSV glycoproteins have been the subject of intense research in development of vaccines useful in preventing or treating HSV infections. See especially, U.S. Pat. Nos. 4,709,011 issued Nov. 24, 1987; 4,762,708 issued Aug. 9, 1988; and 5,149,660 issued Sep. 22, 1992; all to co-inventors herein. In addition, significant effort has been expended in the development of anti-vital agents such as nucleoside analogues and interferons. Nucleoside analogues idoxuridine, trifluridine, vidarabine and acyclovir interfere with HSV genome replication. Interferons interfere with the translation of vital proteins.
While some clinical benefit in ameliorating the sequelae of HSV infection has been achieved by treatment with nucleoside analogues and interferons, therapy with both types of compounds can involve significant side effects. See Fields and Knipe, Eds., Fundamental Virology, Chapter 16, Raven Press, New York, N.Y. (1986). Patients treated with acyclovir, for example, may exhibit local inflammation at silos where the drug is administered, renal dysfunction, and encephalopathic changes. Moreover, HSV mutants resistant to acyclovir have been observed and suppression of recurrences ceases when acyclovir is discontinued [Straus et al., N. Eng. J. Med., 310:1545-1550 (1984)]. Experience in the use of vidarabine has revealed neurologic toxicity. Patients treated with interferon may exhibit fever, fatigue, anorexia, weight loss, nausea and vomiting, bone marrow suppression, pain at injection sites, lymphadenopathy, and mild hair loss. Fibroblast interferon has also been reported to induce the formation of anti-interferon antibodies.
There thus exists a need in the art for additional products useful in preventing or treating HSV infection.